Invasive aspergilosis (IA) is the main cause of nosocomial pneumonia and of death in allogeneic bone marrow (BM) transplants with an infection rate estimated as ranging from 8% to 15% and an associated mortality rate of approximately 90% (3, 16, 30, 36, 47). Despite progress in early diagnosis and therapy with the new anti-fungal agents (6, 31), the majority of cases of AI remain undiagnosed and untreated (16). The most important risk factor for AI historically used to be neutropaenia. However, the advances made in the preparation of patients undergoing chemotherapy and transplantation have led to a significant reduction in the neutropaenia period. Numerous studies have documented that aspergillosis manifests itself following bone marrow transplants concomitantly with the onset of graft-versus-host (GvH) disease (30). The occurrence of IA also in non-neutropaenic patients (17) confirms the importance of specific defects in both the innate and adaptive immune effector mechanisms in the pathogenesis of the disease (13, 20, 22, 32, 39, 43, 44). In particular, the role of Th lymphocytes in providing an essential secondary defence against the fungus has recently been assessed (8-10, 12, 14, 23, 26). Since IA is extremely rare in immunocompetent individuals, therapy aimed at enhancing the host's immune response offers a new and promising approach in the treatment of this infection.
The innate immune system has evolved in a complex, multi-faceted manner to protect lung tissue against infections. The protection of lung tissue is thought to comprise not only a preventive control of microbial proliferation, but also the execution of a balanced inflammatory response sufficient to contain the infection without inducing dangerous degrees of alveolar exudation and infiltration. The molecular components of the alveolar lining have recently been the focus of considerable attention as primary immunomodulators in infections (28, 29).
The pentraxins (PTX) are a superfamily of proteins conserved during the evolution from Limulus polyphemus to man, generally characterised by a pentameric structure (21). PTX3 is a prototype of the long pentraxin that consists in an N-terminal portion coupled to the pentraxin C-terminal domain, the latter being a homologue of the short PTXs (7). PTX3 is secreted by various types of cells, particularly by mononuclear phagocytes, endothelial cells and dendritic cells (DC), in response to the primary inflammatory cytokines in vitro and in vivo (11, 38, 18). Increases in circulating levels of this protein have been detected in various different infectious and inflammatory conditions (37, 19, 34, 41). PTX3 binds a number of selected microbial agents (e.g. A. fumigatus conidia and P. aeruginosa) and activates various effector pathways of the immune system to combat the infectivity of the pathogen (20). Analysis of PTX3-deficient mice has demonstrated that PTX3 is a pattern recognition receptor (PRR) that plays a non-redundant role in the resistance to selected pathogens (20). The susceptibility of PTX3-deficient mice to A. fumigatus has been associated with unsuccessful organisation of the type I adaptive immune response, but is restored by the exogenous administration of recombinant PTX3 (20).
There is a need for therapeutic advances in combating aspergillosis, despite the recent expansion of the antifungal armamentarium (45).
Researchers are beginning to explore new strategies with a singular combination of antifungals and cytokines (46). Treatment with amphotericin B, a first-choice drug, is limited by dose-related nephrotoxity which precludes full-dose therapy in patients who have been submitted to BM transplants (24). Various amphotericin B lipid-based formulations have been developed to reduce the toxicity associated with conventional D-AmB (25), as well as with L-AmB (2). The pharmacokinetic profile of L-AmB toxicity is more favourable than that of D-AmB, thus making full-dose therapy possible. Nevertheless, the failure rate is still a matter for concern (1). Published murine models of IA, in which the efficacy of antifungal agents has been assessed, have relied on neutropaenia induced by chemotherapy with or without corticosteroids to make the mice less susceptible to infection. Recently there has been an increase in the development of new antifungal agents for the treatment of IA, with drug classes characterised by new therapeutic targets (45), which are giving rise to new expectations for the treatment of IA and which increase the number of new combined therapies possible (45). On the basis of the treatment of other infectious diseases (4), combination therapy would appear to be an important therapeutic option.